Time course and localization patterns of interleukin-1beta messenger RNA expression in brain and pituitary after peripheral administration of lipopolysaccharide.
The inflammatory cytokine interleukin-1 has been implicated as a mediator of many centrally controlled responses, such as fever and increased activity of the hypothalamic-pituitary adrenal axis, after systemic infections. To identify the neuroanatomical loci of brain interleukin-1-producing cells during infection, we investigated interleukin-1beta messenger RNA expression by in situ hybridization histochemistry using a 500 nt ribonucleotide probe applied on brain sections from rats injected intraperitoneally with 2.5 mg/kg bacterial lipopolysaccharide or saline. In control animals, interleukin-1beta messenger RNA was not detectable. In the brains of lipopolysaccharide-injected animals, two temporally and spatially distinct waves of interleukin-1beta messenger RNA induction were observed. First, cell labelling appeared at 0.5 h, peaked at 2 h, and declined at 4-8 h. The labelled cells were concentrated in circumventricular organs--organum vasculosum of the lamina terminalis, subfornical organ, median eminence, and area postrema--and in choroid plexus, meninges, and blood vessels. Second, at 8-12 h, scattered small cells became labelled throughout the entire brain parenchyma; the labelling subsided by 24 h. Labelling was not observed in any neurons. In the pituitary, lipopolysaccharide induced strong interleukin-1beta messenger RNA expression initially in the anterior lobe at 0.5-1 h, and later in the neural lobe at 1-2 h, and subsiding thereafter. The results show that at early time points, peripheral lipopolysaccharide induces interleukin-1beta message production at the blood brain barrier and in circumventricular organs where the blood brain barrier is leaky. After a time delay of 6-10 h, however, interleukin-1beta messenger RNA is primarily expressed by non-neuronal cells of the brain in the brain parenchyma. These results suggest that the source of initial brain IL-1 activity after peripheral lipopolysaccharide injection derives from cells of the blood-brain barrier and the circumventricular organs, and the sustained interleukin-1 activity in the central nervous system thereafter is derived from glia.
Quan
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N
Section on Functional Neuroanatomy, National Institute of Mental Health, Bethesda, MD 20892-4070, USA.
Whiteside
M
M
Herkenham
M
M
D000818:Animals; D001345:Autoradiography; D001812:Blood-Brain Barrier; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization; D007375:Interleukin-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger